Patent GB-1416410-A (GB)
Title: Prostaglandin anologues
IPC: C07F9/40
Filed: 1973-12-28
Abstract: 1416410 Prostaglandins ONO PHARMACEUTICAL CO Ltd 28 Dec 1973 [29 Dec 1972 2 Nov 1973] 60040/73 Headings C2C and C2P [Also in Division C3] The invention comprises prostaglandins of the Formulae IX and XXI wherein X is -CH 2 CH 2 - or trans-CH=CH-; R 1  is C 1-10  alkyl or C 1-6  alkyl substituted by a phenyl or a C 5-7  cycloalkyl radical; R 2  is H or C 1-4  alkyl and A is a carbocyclic radical of the formula the C 1-10  alkyl esters and non-toxic salts of such acids, and cyclodextrin clothrates of such acids, esters and alcohols, with the exclusion of trans-2,3-didehydro-PGE 1 , and intermediatesof the Formula XIV wherein R 6  is H or C 1-10  alkyl; Z is or C = O ; and R 3  is 2-tetrahydropyranyl optionally substituted by at least one alkyl radical or 1-ethoxyethyl; their preparation and the preparation of trans-2,3-didehydro-PGE 1 . The compounds are prepared by reacting aldehydes of the Formula X with alkyl phosphonates of the formula wherein R 4  is CH 3  or CH 3 CH 2  and R 5  is C 1-10  alkyl, optionally hydrolysing the resulting compounds of the Formula XIV above in which Z is and R 6  is C 1-10  alkyl, to the corresponding acids, optionally oxidizing the 9α-hydroxy group to oxo, and hydrolysing the tetrahydropyranyloxy or 1-ethoxyethyl groups in the resulting compounds of Formula XIV above, and if desired dehydrating the trans-2,3-didehydro-PGE compounds to the corresponding trans-2,3-didehydro-PGA compounds. Aldehydes of Formula X above are obtained by reducing the methyl esters of the corresponding carbosylic acids, resulting from the esterification of the carboxylic acids, which are obtained by hydrogenating acids of the Formula XVIII prepared by reacting (2-carboxyethyl)triphenylphosphonium bromide with lactols of the Formula XVII obtained by reducing the corresponding lactones, which are made by reacting dihydropyran with the appropriate dihydroxy compounds, resulting from the hydrolysis of the corresponding 5 - acetoxy - 4# - (3 - hydroxy - 3R 1 ,3R 2  - trans- 1 - propenyl) - 3,3α#,4,5,6,6α# - hexahydro - 2H- cyclopenta[b]furan-2-ones. 5α - Acetoxy - 3,3α#,4,5,6,6α# - hexahydro - 4#- (3 - hydroxy - 5 - ethyloct - trans - 1 - enyl) - 2H- cyclopenta[b]furan-2-one is obtained by reducing 5α - acetoxy - 3,3α#,4,5,6,6α# - hexahydro - 4# - (3 - oxo - 5 - ethyloct - trans - 1 - enyl). 2H - cyclopenta[b]furan-2-one, resulting from the reacting between dimethyl 2-oxo-4-ethylheptylphosphonate and 5α - acetoxy - 3,3α#, 4,5,6,6α# - hexahydro - 2 - oxo - 2H - cyclopenta[b]-furan-4#-carboxaldehyde. (2 - Carboxyethyl)triphenylphosphonium bromide is prepared by reacting triphenyl phosphine with 3-bromopropionic acid. Dimethyl 2 - oxo - 4 - ethylheptylphosphonate is obtained by reacting dimethyl methylphosphonate with sec-butyl 2-ethylhexanoate in the presence of butyl lithium. Pharmaceutical compositions suitable for oral, parenteral or rectal administration, contain the above novel prostaglandins of the Formula IX or salts, esters or cyclodextrin clathrates thereof, or prostaglandins of the Formula XXI or cyclodextrin clathrates thereof together with pharmaceutical carriers or coatings. The compounds possess activities similar to those of the naturally occurring prostaglandins.